We are carrying out a genome-wide search to identify chromosome regions that contain genes involved in bipolar affective disorder (BPAD, manic depressive illness). Approximately one percent of the population is afflicted by this severe recurrent mood disorder and untreated patients with BPAD have an approximately 20% risk of death from suicide. We are studying several large families from the Old Order Amish population where there is a very high incidence of BPAD over several generations. In these Old Order Amish families there may be a more limited number of different genes contributing to the affective disorder phenotype. In addition to the other reported linkages for BPAD, (i.e. to chromosomes 4p, 4q, 11,12,18q, 21,22 and X), our results suggest that genes on chromosome 6p SIBPAL (p<0.0001), chromosome 13 SIBPAL (p=0.0003), and chromosome 15 SIBPAL (p=0.0003), have roles in increasing the susceptibility to bipolar affective disorder. Also, rather than limiting our genome-wide search to identifying susceptibility loci for BPAD, we tested the hypothesis that "protective" alleles may contribute to the absence of psychiatric illness (i.e., mental health "wellness") in unaffected family members in these "high risk" families. We found strong evidence for loci on chromosome 4p SIBPAL (p<0.00001; GENEHUNTER NPL=3.8) and 4q SIBPAL (p<0.001; GENEHUNTER NPL=4.7) that are linked to mental health wellness suggesting that certain alleles could prevent or modify the clinical manifestations of BPAD. The identification and characterization of susceptibility and "protective" alleles should lead to the development of more rational and direct approaches to effective therapy for affective disorders.